Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Clinical Advances in Immunotherapy in Myeloma
Webinar 2, July 26, 2017Vaccines for Myeloma
(and Other Advances in Immunotherapy)
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Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Multiple Myeloma Research Foundation
Moderator: • Mary DeRome
Multiple Myeloma Research FoundationNorwalk, Connecticut
www.themmrf.org
https://www.facebook.com/theMMRF
https://twitter.com/theMMRF
https://www.youtube.com/user/TheMMRF
SpeakersKenneth C. Anderson, MDDana-Farber Cancer InstituteBoston, Massachusetts
David Avigan, MDBeth Israel Deaconess Medical CenterBoston, Massachusetts
Noopur Raje, MDMassachusetts General Hospital Boston, Massachusetts
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Topics for Discussion
• What is immunotherapy?• Myeloma vaccines
– What are they?– Vaccination strategies
• Cell-based• Non–cell-based
Immunotherapy
Directing the immune system to fight cancer
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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Why May Myeloma Cells Hide From the Immune System?
They look too much like normal cells and so are not identified as foreign
Antigen presentation on myeloma cells in a way that favors tolerance
Myeloma may inactivate normal T cells
Myeloma may increase presence of immune-inhibiting cells in the tumor microenvironment
Myeloma cells have increased activity of immune-inhibiting pathways
Cancer Immunotherapies Already Available
• mAbs are used in a variety of solid and hematological tumors; examples include Rituxan, Herceptin, Campath
• Vaccines are being used in prostate cancer; one example is Provenge
• Checkpoint inhibitors are being used in melanoma (for example, Yervoy)
mAbs
CheckpointInhibitors
Vaccine
1990s 2000s
mAbs, monoclonal antibodies.
mAbsfor MM!
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Main Targets for Immunotherapy
Directly targeting myeloma cell
markers
Overcoming immune
suppression
Boosting myeloma-fighting
T cells
Activating myeloma-specific
immunity
Monoclonal antibodies
CAR-T cells Vaccines
IMiDs, checkpointinhibitors
Rodriguez-Otero P et al. Haematologica. 2017;102:423.
Cancer Vaccine Therapy
• It is an injection of a combination of myeloma proteins and immune cell-stimulating agents similar to infectious disease vaccines
• It stimulates myeloma-specific T- and B-cell immunity
3. Infuse MM-targeted cells back to MM
patient
2. Modify andexpand cells
in lab1. Extract WBCs
from MM patient
What is it?
How does it work against
myeloma?
Protein BasedCell Based
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Are cancer vaccines the same as other vaccines?
Infectious Vaccines• Administered to healthy
individuals• Existing immune system
intact
Cancer Vaccines• Administered in the presence
of existing cancer• Existing immune system
dysfunction
Cancer vaccines are typically considered therapeutic NOT preventive*
*Vaccination of smoldering MM can be thought of as preventative, as it is attempting to delay or avoid progression to active MM
When are vaccines used during myeloma treatment?
Frontline treatment Maintenance Relapsed
InductionConsolidation/
stem cell transplantation
Maintenance Rescue
Vaccines typically applied after ASCT
with the goal of eliminating any remaining cancer cells
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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The Promise of Effective Cancer Vaccine Strategy
• An immune response that selectively targets malignant cells
• A broad anti-tumor immune response has the potential to target the different tumor clones, including malignant stem cell populations
• Immune response provides the potential for memory and long-term surveillance
Overcoming the Tumor Microenvironment
Davies M. Cancer Manag Res. 2014;6:63.
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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Cancer Vaccine Strategies
Berzofsky JA et al. J Clin Invest. 2004;113:1515.
Designing a Cancer Vaccine: Choosing the Right Target to Load Dendritic Cells
• Selecting the right targets– Shared: NY-ESO, MUC1,
XBP1, SOX2, WT1, PRAME, Survivin
– Patient Specific • Idiotype• Neoantigens
1. Infect APC with DNA from MM cells
2. Loading of MM cell peptides on surface of APC
3. Loading of MM cell lysate
Myeloma cell
APC
4. Myeloma cell fusion
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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DC/Tumor Fusion Vaccine
Adherent PBMCs cultured for 5-7 days with GM-CSF & IL-4; TNF- added for 48-72 hours
Myeloma cellsisolated
DCs assessed for DC & tumor specific markers
Myeloma cells assessed for tumor & DC specific markers
DC & myeloma fused with 50% PEG at DC: tumor, 3:1 to 10:1
Fusion cells quantified by measuring dual expression ofunique DC & tumor markers
Doses prepared & frozen microbiology testing sent
Leukapharesis
CD38
MUC1
DR
CD86
CD86
CD38
CD40
CD83
CD80
CD138
CD138
GM-CSF 100ugat vaccine site for 4 days
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Rosenblatt J et al Blood. 2011;117:393.
Vaccination Induces T Cell and Antibody Responses Targeting Myeloma Cells
Vaccination-Induced Expansion of Myeloma-Reactive T Cells and
Targeting of Minimal Residual Disease
29%
54%
38%
25%
33% 13%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
100 Day Post-Transplant Post 100 Day (Best Response)
% P
arti
cip
ants
CR/nCR VGPR PR
Rosenblatt J et al. Clin Cancer Res. 2013;19:3640.
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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MM initial therapy
Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Revlimid Maintenance for Multiple Myeloma with or without
Vaccination with Dendritic Cell (DC)/Myeloma Fusions (MY T VAX)
Ran
do
miz
atio
n
MMel200AutoHCT
Dendriticcell
collection
Tumor cell collection
HCT
2 3 4
En
rollm
ent
2
Vaccinations + GM-CSF + Rev
1 6 7 85 10 119
d56
d90
2 3 41 6 7 85 10 119
En
rollm
ent
1
2 3 41 6 7 85 10 119
Ass
essm
ent
of
CR
Rev + GM-CSF
Rev Alone
2
1
1
BMT CTN 1401 Trial.Investigators: David Avigan, Nina Shah, David Chung, Marcelo Pasquini
Cell-Based Myeloma Vaccines
VaccineNo.
PatientsRoute of
Administration Results
Idiotype-pulsed dendritic cells1* 12 IV 17% in CR
Idiotype-pulsed dendritic cells2* 26 IV 65% alive at 30 mos
Idiotype-pulsed dendriticcells3* 27 IV
Median OS 5.3 yrs (vs. 3.4 yrs for unvaccinated patients)
MAGE3-, survivin-, or BCMA-mRNA-loaded dendritic cells4* 12 IV and ID 83% OS at 55 mos
Dendritic cell/tumor cell fusion5 18 SC 69% with SD
Dendritic cell/tumor cell fusion6 24 SC
47% CR/nCR78% CR/VGPR
*Following ASCT1. Reichardt VL et al. Blood. 1999;93:2411.2. Liso A et al. Biol Blood Marrow Transplant. 2000;6:621.3. Lacy MQ et al. Am J Hematol. 2009;84:799.
4. Hobo W et al. Cancer Immunol Immunother. 2013;62:1381.5. Rosenblatt J et al. Blood. 2011;117:393.6. Rosenblatt J et al. Clin Cancer Res. 2013;19:3640.
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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Myeloma GVAX Vaccine
*GVAX is a GM-CSF–based vaccine consisting of 2 allogeneic cell lines: H929 and U266, coupled to a GM-CSF–secreting bystander cell line, K562/GM
Borrello I et al. Blood. 2015;126: Abstract 4238.
MM patients on a Revlimid-containing regimen
(RVD, Rd, BiRD, or R)
Single-agent Revlimid + GVAX*
15 patients evaluated
nCR
The generation of tumor-specific immunity in a low disease burden state can significantly delay relapse. A larger randomized phase 2
study will attempt to answer this question.
median PFSnot yet reached
Combination Immunotherapy and the Role of Checkpoint Inhibition
Checkpoint inhibitor
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Types of Cancer Vaccines: Non–Cell-Based
Recombinant proteins Mutation-based
Myeloma cells
Genomic sequencing
Identify mutations
Synthesize mutant peptidesPeptides + adjuvant = vaccine
Multiple vaccinations stimulate T and B cells
Proteins isolated from
myeloma cells in lab, injected into myeloma
patient
Myeloma cells
Myeloma peptides
Myeloma peptide genes (for example, WT)
Peptides + adjuvant = vaccine
Multiple vaccinations stimulate T and B cells
Proteins made in a lab, injected into
myeloma patient
Non–Cell-Based Vaccines: Recombinant Proteins
• A high frequency of vaccine-specific T-cell responses were generated after transplant
MAGE-A3 Peptide Vaccine1
• A small phase 1 study of 18 patients showed encouraging results in overall and progression-free survival
• A phase 2 study is planned
WT-1 Vaccine2
• Studied in smoldering MM patients at high risk of progressing to active MM
• PVX-410 was well-tolerated
• An immune response to PVX-410 was seen with PVX-410 alone, which was enhanced by the addition of Revlimid
PVX-410 Vaccine3
1. Rapoport AP et al. Clin Cancer Res. 2014;20:1355.2. Koehne G et al. J Clin Oncol. 2017;35: Abstract 8016.3. Nooka AK et al. Blood. 2017;128: Abstract 2124.
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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WK 0 WK 2 WK 4 WK 6 WK 8 Wk 10 … WK 14 ……. WK 22Baseline Post-2V Post- 4V Post- 6V (1M FW) (3 M FW)
1 V 2 V 3 V 4 V 5 V 6 V
Immune monitor
WK 0 WK 2 WK 4 WK 6 WK 8 Wk 10 … WK 14 ……. WK 22Baseline Post-2V Post- 4V Post- 6V (1M FW) (3 M FW)
1 V 2 V 3 V 4 V 5 V 6 V
Revlimid
Cycle 2
Revlimid
Cycle 3
28 days (4 W)/cycle (21 day trt, 7 day rest)
Revlimid
Cycle 1
WK 11
* No Len for 3 weeks
PVX-410 Multi-Peptide Vaccine Study Schema: SMM Patients
XBP1-1 peptides: spliced and unspliced variant, CD138 and CS1
Cohort 1: Vaccine Alone
Cohort 2: Vaccine
+ Revlimid
PVX-410 Multi-Peptide Vaccine Study: Immune Responses
Vaccine Alone (Cohort 1)
Gated: Total CD3+CD8+ T cells
Vaccine + Len (Cohort 2)Vaccine (Cohort 1)
Gated: Total CD3+CD8+ T cells
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Stimulator: XBP1us / XBP1sp / CD138 / CS1 Peptides
Baseline (Wk 0) Post-2 Vac (Wk 4) Post-4 Vac (Wk 8)
Post- 6 Vac (1M FW) Post- 6 Vac (3M FW) SUMMARY SUMMARY
Induction of XBP1/CD138/CS1
Peptides-Specific CTLby Vaccine
Vaccine Gradually InducesXBP1/CD138/CS1-Specific Cytotoxic T
Lymphocytes (CTL) in SMM Patient
PVX-410 Multi-Peptide Vaccine Study: Clinical Response Summary
*1 patient who achieved an MR later progressed to active disease at 5 months post treatment
PVX-410PVX-410 + Revlimid
Status, no. patientsActive treatmentFollow-upCompleted/off study
0012
00
9/1
Disease responses, no. patients (%)Overall best clinical response (≥MR)Best response (≥PR)Stable diseaseProgressive disease
0/12 (0%)0/12 (0%)7/12 (58%)5/12 (42%)
4/9* (44%)1/9 (11%)4/9 (44%)1/9* (11%)
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
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Ongoing Clinical Trials of Myeloma Vaccines
TrialStudyPhase Site(s)
Survivin Vaccine 1 H. Lee Moffitt Cancer Center
Vaccination with PD-L1 Peptide 1 Non-US
Enhancing Anti-Myeloma Vaccine Response After Autologous Stem Cell Transplantation 2 Emory University
Dendritic Cell/Myeloma Fusion Vaccine 2 National Heart, Lung, and Blood Institute (NHLBI) (CTN 1401)
SVN53-67/M57-KLH Peptide Vaccine in Treating Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide Maintenance Therapy
1 Roswell Park Cancer Institute
CT7, MAGE-A3, and WT1 mRNA-electroporated Autologous Langerhans-type Dendritic Cells as Consolidation 1 MSKCC
A Study of PVX-410, a Cancer Vaccine, and Durvalumab +/-Lenalidomide for Smoldering MM 1 Massachusetts General
Hospital
Vaccine Therapy With or Without Cyclophosphamide in Treating Patients With Recurrent or Refractory Multiple Myeloma 1/2 Mayo Clinic
Questions & Answers
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Closing
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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Resources for You!
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Upcoming MMRF WebinarsSeries Topic Date Time
ImmunotherapyEngineered ImmuneCells
August 9, 2017 1:00 PM ET
Hot Topic
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September 20, 2017 1:00 PM ET
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For more information or to register, visit: theMMRF.org/webinars
Clinical Advances in Immunotherapy in Myeloma Webinar 2: Vaccines for Myeloma (and Other Advances in Immunotherapy)
7/26/17
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MMRF Multiple Myeloma SummitsFall 2017
Saturday, September 16, 2017Chicago, IllinoisAndrzej Jakubowiak, MD–ChairUniversity of Chicago Medical Center
Saturday, October 14, 2017Charlotte, North CarolinaSaad Z. Usmani, MD−Chair
Friday, November 3, 2017 New York City, New York Ajai Chari, MD–Chair Mount Sinai Health System Tisch Cancer InstituteMount Sinai School of Medicine Levine Cancer Institute
Saturday, November 18, 2017Los Angeles, CaliforniaJames Berenson, MD–Co-Chair Institute for Myeloma and Bone
Cancer Research
Amrita Y. Krishnan, MD–Co-ChairJudy and Bernard Briskin Center for
Multiple Myeloma ResearchCity of Hope Medical Center
To register, please visit:theMMRF.org/Patient
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